N12-乙基取代吲哚咔唑衍生物的合成及细胞毒活性研究
收稿日期: 2016-02-29
修回日期: 2016-04-17
网络出版日期: 2016-05-03
基金资助
国家自然科学基金（Nos. 81561148012，41376148，81273532，30973680）、高科技发展计划（No. 2012AA092104）以及国家自然科学基金-广东联合基金（No. U1501221）资助项目.
Synthesis and Cytotoxicity of N12-Ethyl Substituted Indolocarbazole Derivatives
Received date: 2016-02-29
Revised date: 2016-04-17
Online published: 2016-05-03
Supported by
Project supported by the National Natural Science Foundation of China (Nos. 81561148012, 41376148, 81273532, 30973680), the National High-Tech R&D Program of China (No. 2012AA092104), and the National Natural Science Foundation of China-Guangdong Fund Joint Project (No. U1406402).
合成了9个新的N12-乙基取代吲哚咔唑衍生物6～14，其结构经1H NMR、13C NMR和HRESIMS确定. 用噻唑蓝（MTT）法测试了衍生物对人肺癌细胞A549、肝癌细胞HepG-2和宫颈癌细胞Hela的细胞毒活性. 用细胞计数试剂 盒-8（Cell Counting Kit-8，CCK-8）法测试了衍生物对白血病细胞K562的细胞毒活性. 结果显示，化合物7～9对K562的细胞毒活性与阳性对照阿霉素（ADM）相近，半数抑制浓度（IC50）为0.43～0.93 μmol/L. 化合物8和12对Hela的活性与阳性对照相近，IC50分别为1.23和0.43 μmol/L. 化合物13的盐酸盐14对所测试的4种肿瘤细胞株均有较强的抑制活性，IC50值在0.23～1.72 μmol/L之间，可作为抗肿瘤先导化合物进行深入研究.
关键词： N12-乙基吲哚咔唑; 合成; 肿瘤细胞毒活性
马红光 , 王立平 , 徐志红 , 张亚鹏 , 李霞 , 朱伟明 . N12-乙基取代吲哚咔唑衍生物的合成及细胞毒活性研究[J]. 有机化学, 2016 , 36(8) : 1839 -1846 . DOI: 10.6023/cjoc201602035
Nine new N12-ethyl substituted indolocarbazole derivatives were synthesized. Their structures were identified by 1H NMR, 13C NMR and HRESIMS. The thiazolyl blue tetrazolium bromide (MTT) method was used to evaluate the cytotoxicities of these derivatives against A549, HepG-2 and Hela cell lines, while the cell counting kit-8 (CCK-8) method was used to evaluate cytotoxicity against K562 cell lines. The results showed that compounds 7～9 displayed comparable cytotoxicity to adriamycin (ADM) against K562 cell lines with the IC50 values of 0.43～0.93 μmol/L. Compounds 8 and 12 showed comparable cytotoxicity to ADM against Hela cell lines with the IC50 values of 1.23 and 0.43 μmol/L, respectively. The hydrochloride 14 of compound 13 exhibited good cytotoxicity against the four cell lines with the IC50 values of 0.23～1.72 μmol/L, indicating a worth of further study as an antitumor lead compound.
Key words： N12-ethyl indolocarbazole; synthesis; cytotoxicity
[1] Zhao, C.; Zhu, T.; Zhu, W. Chin. J. Org. Chem. 2013, 33, 1195 (in Chinese).
(赵成英, 朱统汉, 朱伟明, 有机化学, 2013, 33, 1195.)
[2] Ma, H.; Liu, Q.; Zhu, G.; Liu, H.; Zhu, W. J. Asian Nat. Prod. Res. 2016, 18, 92.
[3] Zhao, C.; Liu, H.; Zhu, W. Acta Microbiol. Sin. 2016, 56, 331 (in Chinese).
(赵成英, 刘海珊, 朱伟明, 微生物学报, 2016, 56, 331.)
[4] Zhu, T. H.; Ma, Y. N.; Wang, W. L.; Chen, Z. B.; Qin, S. D.; Du, Y. Q.; Wang, D. Y.; Zhu, W. M. Chin. J. Mar. Drugs 2015, 34, 56 (in Chinese).
(朱统汉, 马颖娜, 王文玲, 陈正波, 秦世冬, 杜玉琪, 王冬阳, 朱伟明, 中国海洋药物, 2015, 34, 56.)
[5] Omura, S.; Iwai, Y.; Hirano, A.; Nakagawa, A.; Awaya, J.; Tsuchiya, H.; Takahashi, Y.; Masuma, R. J. Antibiot. 1977, 30, 275.
[6] Wang, L.; Zhuang, Y.; Sun, K.; Zhu, W. Chin. J. Org. Chem. 2014, 34, 1603 (in Chinese).
(王立平, 庄以彬, 孙坤来, 朱伟明, 有机化学, 2014, 34, 1603.)
[7] Wang, L.; Mei, X.; Wang, C.; Zhu, W. Tetrahedron 2015, 71, 7990.
[8] Gani, O. A.; Engh, R. A. Nat. Prod. Rep. 2010, 27, 489.
[9] Sánchez, C.; Méndez, C.; Salas, J. A. Nat. Prod. Rep. 2006, 23, 1007.
[10] Fu, P.; Zhuang, Y.; Wang, Y.; Liu, P.; Qi, X.; Gu, K.; Zhang, D.; Zhu, W. Org. Lett. 2012, 14, 6194.
[11] Fu, P.; Yang, C.; Wang, Y.; Liu, P.; Ma, Y.; Xu, L.; Su, M.; Hong, K.; Zhu, W. Org. Lett. 2012, 14, 2422.
[12] Pereira, E. R.; Belin, L.; Sancelme, M.; Prudhomme, M.; Ollier, M.; Rapp, M.; Severe, D.; Riou, J. F.; Fabbro, D.; Meyer, T. J. Med. Chem. 1996, 39, 4471.
[13] Labourier, E.; Riou, J. F.; Prudhomme, M.; Carrasco, C.; Bailly, C.; Tazi, J. Cancer Res. 1999, 59, 52.
[14] Zhu, G. X.; Conner, S. E.; Zhou, X.; Chan, H. K.; Shih, C.; Engler, T. A.; Al-Awar, R. S.; Brooks, H. B.; Watkins, S. A.; Spencer, C. D.; Schultz, R. M.; Dempsey, J. A.; Considine, E. L.; Patel, B. R.; Ogg, C. A.; Vasudevan, V.; Lytle, M. L. Bioorg. Med. Chem. Lett. 2004, 14, 3057.
[15] Zhang, H. C.; White, K. B.; Ye, H.; McComsey, D. F.; Derian, C. K.; Addo, M. F.; Andrade-Gordon, P.; Eckardt, A. J.; Conway, B. R.; Westover, L.; Xu, J. Z.; Look, R.; Demarest, K. T.; Emanuel, S.; Maryanoff, B. E. Bioorg. Med. Chem. Lett. 2003, 13, 3049.
[16] Rodriguez-Ariza, A.; Lopez-Pedrera, C.; Aranda, E.; Barbarroja, N. Crit. Rev. Oncol. Hematol. 2011, 80, 241.
[17] Hudkins, R. L.; Becknell, N. C.; Zulli, A. L.; Underiner, T. L.; Angeles, T. S.; Aimone, L. D.; Albom, M. S.; Chang, H.; Miknyoczki, S. J.; Hunter, K.; Jones-Bolin, S.; Zhao, H.; Bacon, E. R.; Mallamo, J. P.; Ator, M. A.; Ruggeri, B. A. J. Med. Chem. 2012, 55, 903.
[18] Ruegg, U. T.; Burgess, G. M. Trends Pharmacol. Sci. 1989, 10, 218.
[19] Bharate, S. B.; Sawant, S. D.; Singh, P. P.; Vishwakarma, R. A. Chem. Rev. 2013, 113, 6761.
[20] Anastassiadis, T.; Deacon, S. W.; Devarajan, K.; Ma, H.; Peterson, J. R. Nat. Biotechnol. 2011, 29, 1039.
[21] Huang, Y. C.; Chao, D. K.; Chao, K. S. C.; Chen, Y. J. Toxicol. In Vitro 2009, 23, 979.
[22] Del Corral, A.; Dutreix, C.; Huntsman-Labed, A.; Lorenzo, S.; Morganroth, J.; Harrell, R.; Wang, Y. Cancer Chemother. Pharmacol. 2012, 69, 1255.
[23] Fischer, T.; Stone, R. M.; Deangelo, D. J.; Galinsky, I.; Estey, E.; Lanza, C.; Fox, E.; Ehninger, G.; Feldman, E. J.; Schiller, G. J.; Klimek, V. M.; Nimer, S. D.; Gilliland, D. G.; Dutreix, C.; Huntsman-Labed, A.; Virkus, J.; Giles, F. J. J. Clin. Oncol. 2010, 28, 4339.
[24] Graul, A. I. Drug News Perspect. 2007, 20, 45.
[25] Levis, M.; Allebach, J.; Tse, K. F., Zheng, R.; Baldwin, B. R.; Smith, B. D.; Jones-Bolin, S.; Ruggeri, B.; Dionne, C.; Small, D. Blood 2002, 99, 3885.
[26] Diaz, T.; Navarro, A.; Ferrer, G.; Gel, B.; Gaya, A.; Artells, R.; Bellosillo, B.; Garcia-Garcia, M.; Serrano, S.; Martínez, A.; Monzo, M. PLoS One 2011, 6, e18856.
[27] Marshall, J. L.; Kindler, H.; Deeken, J.; Bhargava, P.; Vogelzang, N. J.; Rizvi, N.; Luhtala, T.; Boylan, S.; Dordal, M.; Robertson, P.; Hawkins, M. J.; Ratain, M. J. Invest New Drugs 2005, 23, 31.
[28] Knapper, S.; Burnett, A. K.; Littlewood, T.; Kell, W. J.; Agrawal, S.; Chopra, R.; Clark, R.; Levis, M. J.; Small, D. Blood 2006, 108, 3262.
[29] Mackay, H. J.; Twelves, C. J. Nat. Rev. Cancer 2007, 7, 554.
[30] Lee, K. W.; Kim, S. G.; Kim, H. P.; Kwon, E.; You, J.; Choi, H. J.; Park, J. H.; Kang, B. C.; Im, S. A.; Kim, T. Y.; Kim, W. H.; Bang, Y. J. Cancer Res. 2008, 68, 1916.
[31] Padda, S. K.; Krupitskaya, Y.; Chhatwani, L.; Fisher, G. A.; Colevas, A. D.; Pedro-Salcedo, M. S.; Decker, R.; Latz, J. E.; Wakelee, H. A. Cancer Chemother. Pharmacol. 2012, 69, 1013.
[32] Slater, M. J.; Baxter, R.; Bonser, R. W.; Cockerill, S.; Gohil, K.; Parry, N.; Robinson, E.; Randall, R.; Yeates, C.; Snowden, W.; Walters, A. Bioorg. Med. Chem. Lett. 2001, 11, 1993.
[33] Sanchez-Martinez, C.; Shih, C.; Zhu, G. X.; Li, T. C.; Brooks, H. B.; Patel, B. K.; Schultz, R. M.; DeHahn, T. B.; Spencer, C. D.; Watkins, S. A.; Ogg, C. A.; Considine, E.; Dempsey, J. A.; Zhang, F. M. Bioorg. Med. Chem. Lett. 2003, 13, 3841.
[34] Zhang, M.; Sheng, C. Q.; Xu, H.; Song, Y. L.; Zhang, W. N. Sci. China, Ser B: Chem. 2007, 37, 288 (in Chinese).
(张珉, 盛春泉, 徐辉, 宋云龙, 张万年, 中国科学(B辑): 化学, 2007, 37, 288.)
[35] Davis, P. D.; Bit, R. A.; Hurst, S. A. Tetrahedron Lett. 1990, 31, 2353.
[36] Haddach, A. A.; Kelleman, A.; Deaton-Rewolinski, M. V. Tetrahedron Lett. 2002, 43, 399.
[37] Joyce, R. P.; Gainor, J. A.; Weinreb, S. M. J. Org. Chem. 1987, 52, 1177.
[38] Julia, M.; Tchernoff, G. Bull. Soc. Chim. Fr. 1960, 741.
[39] Bocchi, V.; Casnati, G.; Dossena, A.; Villani, F. Synthesis 1976, 414.
Lakatosh, S. A.; Balzarini, J.; Andrei, G.; Snoeck, R.; Lakatosh, A.; De Clercq, E.; Preobrazhenskaya, M. N. J. Antibiot. 2002, 55, 768.
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